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This study developed and validated a surgical instrument motion measurement system for skill evaluation during practical laparoscopic surgery training. Owing to the various advantages of laparoscopic surgery including minimal invasiveness, this technique has been widely used. However, expert surgeons have insufficient time for providing training to beginners due to the shortage of surgeons and limited working hours. Skill transfer efficiency has to be improved for which there is an urgent need to develop objective surgical skill evaluation methods. Therefore, a simple motion capture-based surgical instrument motion measurement system that could be easily installed in an operating room for skill assessment during practical surgical training was developed. The tip positions and orientations of the instruments were calculated based on the marker positions attached to the root of the instrument. Because the patterns of these markers are individual, this system can track multiple instruments simultaneously and detect exchanges. However due to the many obstacles in the operating room, the measurement data included noise and outliers. In this study, the effect of this decrease in measurement accuracy on feature calculation was determined. Accuracy verification experiments were conducted during wet-lab training to demonstrate the capability of this system to measure the motion of surgical instruments with practical accuracy. A surgical training experiment on a cadaver was conducted, and the motions of six surgical instruments were measured in 36 cases of laparoscopic radical nephrectomy. Outlier removal and smoothing methods were also developed and applied to remove the noise and outliers in the obtained data. The questionnaire survey conducted during the experiment confirmed that the measurement system did not interfere with the surgical operation. Thus, the proposed system was capable of making reliable measurements with minimal impact on surgery. The system will facilitate surgical education by enabling the evaluation of skill transfer of surgical skills.

Gestational diabetes mellitus (GDM) in human patients disrupts glucose metabolism post-pregnancy, affecting fetal development. Although obesity and genetic factors increase GDM risk, a lack of suitable models impedes a comprehensive understanding of its pathology. To address this, we administered streptozotocin (STZ, 75 mg/kg) to C57BL/6N mice for two days before pregnancy, establishing a convenient GDM model. Pregnant mice exposed to STZ (STZ-pregnant) were compared with STZ-injected virgin mice (STZ-virgin), citrate buffer-injected virgin mice (CB-virgin), and pregnant mice injected with citrate buffer (CB-pregnant). STZ-pregnant non-obese mice exhibited elevated blood glucose levels on gestational day 15.5 and impaired glucose tolerance. They also showed fewer normal fetuses compared to CB-pregnant mice. Additionally, STZ-pregnant mice had the highest plasma C-peptide levels, with decreased pancreatic islets or increased alpha cells compared to CB-pregnant mice. Kidneys isolated from STZ-pregnant mice did not display histological alterations or changes in gene expression for the principal glucose transporters (GLUT2 and SGLT2) and renal injury-associated markers. Notably, STZ-pregnant mice displayed decreased gene expression of insulin-receiving molecules (ISNR and IGFR1), indicating heightened insulin resistance. Liver histology in STZ-pregnant mice remained unchanged except for a pregnancy-related increase in lipid droplets within hepatocytes. Furthermore, the duodenum of STZ-pregnant mice exhibited increased gene expression of ligand-degradable IGFR2 and decreased expression of GLUT5 and GLUT12 (fructose and glucose transporters, respectively) compared to STZ-virgin mice. Thus, STZ-pregnant mice displayed GDM-like symptoms, including fetal abnormalities, while organs adapted to impaired glucose metabolism by altering glucose transport and insulin reception without histopathological changes. STZ-pregnant mice offer a novel model for studying mild onset non-obese GDM and species-specific differences in GDM features between humans and animals.

How do voters react to an ongoing natural threat? Do voters sanction or reward incumbents even when incumbents cannot be held accountable because an unforeseeable natural disaster is unfolding? We address this question by investigating voters' reactions to the early spread of COVID-19 in the 2020 French municipal elections. Using a novel, fine-grained measure of the circulation of the virus based on excess-mortality data, we find that support for incumbents increased in areas that were particularly hard hit by the virus. Incumbents from both left and right gained votes in areas more strongly affected by COVID-19. We provide suggestive evidence for two mechanisms that can explain our findings: an emotional channel related to feelings of fear and anxiety, and a prospective-voting channel, related to the ability of incumbents to act more swiftly against the diffusion of the virus than challengers.

The histomorphological features of normal kidneys in cats and dogs have been revealed despite the high susceptibility of cats to tubulointerstitial damage. Herein, the histological characteristics of the two species were compared. Cytoplasmic lipid droplets (LDs) were abundant in the proximal convoluted tubules (PCTs) of cats aged 23–27 months but scarce in dogs aged 24–27 months. LDs were rarely observed in the distal tubules (DTs) and collecting ducts (CDs) of either species, as visualized by the expression of Tamm–Horsfall protein 1, calbindin-D28K, and aquaporin 2. The occupational area ratio of proximal tubules (PTs) in the renal cortex was higher, but that of DTs or CDs was significantly lower in adult cats than in dogs. Single PT epithelial cells were larger, but PCT, DT, and CD lumens were significantly narrower in adult cats than in dogs. Unlike adults, young cats at 6 months exhibited significantly abundant cytoplasmic LDs in proximal straight tubules, indicating lipid metabolism-related development. Histochemistry of the 21 lectins also revealed variations in glycosylation across different renal tubules and CDs in both species. Sodium-glucose cotransporter 2 was expressed only in PTs, excluding the proximal straight tubules with few LDs in adult cats or the PCTs of young cats and adult dogs. These findings are crucial for understanding species-specific characteristics of renal histomorphology and pathogenesis. [ABSTRACT FROM AUTHOR]

This study developed and validated a surgical instrument motion measurement system for skill evaluation during practical laparoscopic surgery training. Owing to the various advantages of laparoscopic surgery including minimal invasiveness, this technique has been widely used. However, expert surgeons have insufficient time for providing training to beginners due to the shortage of surgeons and limited working hours. Skill transfer efficiency has to be improved for which there is an urgent need to develop objective surgical skill evaluation methods. Therefore, a simple motion capture–based surgical instrument motion measurement system that could be easily installed in an operating room for skill assessment during practical surgical training was developed. The tip positions and orientations of the instruments were calculated based on the marker positions attached to the root of the instrument. Because the patterns of these markers are individual, this system can track multiple instruments simultaneously and detect exchanges. However due to the many obstacles in the operating room, the measurement data included noise and outliers. In this study, the effect of this decrease in measurement accuracy on feature calculation was determined. Accuracy verification experiments were conducted during wet-lab training to demonstrate the capability of this system to measure the motion of surgical instruments with practical accuracy. A surgical training experiment on a cadaver was conducted, and the motions of six surgical instruments were measured in 36 cases of laparoscopic radical nephrectomy. Outlier removal and smoothing methods were also developed and applied to remove the noise and outliers in the obtained data. The questionnaire survey conducted during the experiment confirmed that the measurement system did not interfere with the surgical operation. Thus, the proposed system was capable of making reliable measurements with minimal impact on surgery. The system will facilitate surgical education by enabling the evaluation of skill transfer of surgical skills. [ABSTRACT FROM AUTHOR]

A unique historical architecture was created at Shuri Castle (Shuri-jo) in the Ryukyu Islands by its "Kawara" roof tiles. After the 13th and 14th centuries, Kawara tiles were introduced to the Ryukyu Islands from several regions, including China, Korea, and mainland Japan, and evolved shapes and patterns that are unique to this island region. However, the transition of some internal features, such as the chemical components and microstructure, had not been analyzed. This study used a multi-faceted approach for such internal data and non-destructive quantitative methods to propose a new perspective on the evolution of historical Ryukyuan Kawara. We analyzed two styles of Ryukyuan Kawara from the 13th to 15th centuries and found that the material processing and firing conditions of the two styles were very similar, even though it had been suggested that they had different origins. A quantitative analysis of tiles from the 16th to 19th centuries revealed a transition in color tone to red, leading to the modern traditional Ryukyuan tiles; traces of changes in firing conditions were also found along with this transition. Finally, the study revealed that the evolution of Ryukyuan Kawara consisted of changed factors, e.g. surface color, and unchanged factors, e.g. paste density. Previous archaeological studies mainly focused on changing external characteristics, such as form and pattern; however, our analysis showed that the internal features changed, while the elemental composition and paste density remained constant from the appearance of the roof tiles until the 19th century. We propose that this is related to different responses of individual factors to external stressors, such as the social context, which may be common to other archaeological artifacts as well. Our study provides a new perspective on the evolution of Ryukyuan Kawara and presents a different discussion of and methods for the chronological study of material culture.

The purpose of this study was to characterize the motion features of surgical devices associated with laparoscopic surgical competency and build an automatic skill-credential system in porcine cadaver organ simulation training. Participants performed tissue dissection around the aorta, dividing vascular pedicles after applying Hem-o-lok (tissue dissection task) and parenchymal closure of the kidney (suturing task). Movements of surgical devices were tracked by a motion capture (Mocap) system, and Mocap-metrics were compared according to the level of surgical experience (experts: ≥50 laparoscopic surgeries, intermediates: 10–49, novices: 0–9), using the Kruskal-Wallis test and principal component analysis (PCA). Three machine-learning algorithms: support vector machine (SVM), PCA-SVM, and gradient boosting decision tree (GBDT), were utilized for discrimination of the surgical experience level. The accuracy of each model was evaluated by nested and repeated k-fold cross-validation. A total of 32 experts, 18 intermediates, and 20 novices participated in the present study. PCA revealed that efficiency-related metrics (e.g., path length) significantly contributed to PC 1 in both tasks. Regarding PC 2, speed-related metrics (e.g., velocity, acceleration, jerk) of right-hand devices largely contributed to the tissue dissection task, while those of left-hand devices did in the suturing task. Regarding the three-group discrimination, in the tissue dissection task, the GBDT method was superior to the other methods (median accuracy: 68.6%). In the suturing task, SVM and PCA-SVM methods were superior to the GBDT method (57.4 and 58.4%, respectively). Regarding the two-group discrimination (experts vs. intermediates/novices), the GBDT method resulted in a median accuracy of 72.9% in the tissue dissection task, and, in the suturing task, the PCA-SVM method resulted in a median accuracy of 69.2%. Overall, the mocap-based credential system using machine-learning classifiers provides a correct judgment rate of around 70% (two-group discrimination). Together with motion analysis and wet-lab training, simulation training could be a practical method for objectively assessing the surgical competence of trainees.

This paper describes a detailed study of the spectral homogeneity of human platelets using Surface-enhanced Raman spectroscopy (SERS). We used a combined approach based on multivariate methods as principal component analysis and pair correlation algorithms to investigate platelets spectral properties. The correlation coefficients for each sample have been calculated, and the average coefficient of determination has been estimated. The high degree of spectral homogeneity inside one probe and between them has been revealed. The prospects of obtained results usage for pathologies based on platelet conformations during cardiovascular diseases have been demonstrated.

When selecting the nasotracheal tube diameter for nasotracheal intubation, atraumatic introduction of the tube through the nasal passage and a safe location of the tube's cuff and tip should be ensured simultaneously. To maintain safety margin for the tube's cuff and tip from the vocal cords and carina (2 cm and 3 cm, respectively), the maximum allowable proximal-cuff-to-tip distance was calculated as 5 cm less than the measured vocal cords-to-carina distance. The primary aim of this study was to find a single predictive preoperative factor of the nostril size and maximum allowable proximal-cuff-to-tip distance of nasotracheal tubes. The secondary aim was to compare the difference in the safety margin between the maximum allowable proximal-cuff-to-tip distance based on the patient's airway and the actual proximal-cuff-to-tip distance of the selected tube. We used fiberoptic bronchoscope to measure the distance from the vocal cords to the carina for the calculation of the maximum allowable proximal-cuff-to-tip distance. We analyzed the association of preoperative characteristics such as age, sex, height, and weight with the nostril size and maximum allowable proximal-cuff-to-tip distance. The proportion of patients with appropriate locations of both the cuff and tip was evaluated. Sex and height were significant predictive factors of the nostril size and maximum allowable proximal-cuff-to-tip distance, respectively (p = 0.0001 and p = 0.0048). The difference in the safety margin was significantly decreased when the tube diameter was selected based on the nostril size rather than by sex (p

Hemorrhage, a main cause of mortality in patients with trauma, affects vital signs such as blood pressure and heart rate. Shock index (SI), calculated as heart rate divided by systolic blood pressure, is widely used to estimate the shock status of patients with hemorrhage. The difference in SI between the emergency department and prehospital field can indirectly reflect urgency after trauma. We aimed to determine the association between delta SI (DSI) and in-hospital mortality in patients with torso or extremity trauma. Patients with DSI >0.1 are expected to be associated with high mortality. This retrospective, observational study used data from the Pan-Asian Trauma Outcomes Study. Patients aged 18–85 years with abdomen, chest, upper extremity, lower extremity, or external injury location were included. Patients from China, Indonesia, Japan, Philippines, Thailand, and Vietnam; those who were transferred from another facility; those who were transferred without the use of emergency medical service; those with prehospital cardiac arrest; those with unknown exposure and outcomes were excluded. The exposure and primary outcome were DSI and in-hospital mortality, respectively. The secondary and tertiary outcome was intensive care unit (ICU) admission and massive transfusion, respectively. Multivariate logistic regression analysis was performed to test the association between DSI and outcome. In total, 21,534 patients were enrolled according to the inclusion and exclusion criteria. There were 3,033 patients with DSI >0.1. The in-hospital mortality rate in the DSI >0.1 and ≤0.1 groups was 2.0% and 0.8%, respectively. In multivariate logistic regression analysis, the DSI ≤0.1 group was considered the reference group. The unadjusted and adjusted odds ratios of in-hospital mortality in the DSI >0.1 group were 2.54 (95% confidence interval [CI] 1.88–3.42) and 2.82 (95% CI 2.08–3.84), respectively. The urgency of traumatic hemorrhage can be determined using DSI, which can help hospital staff to provide proper trauma management, such as early trauma surgery or embolization.

This paper describes a detailed study of spectral and time-resolved photoprocesses in human platelets and their complexes with platinum (Pt) nanoparticles (NPs). Fluorescence, quantum yield, and platelet amino acid lifetime changes in the presence and without femtosecond ablated platinum NPs have been studied. Fluorescence spectroscopy analysis of main fluorescent amino acids and their residues (tyrosine (Tyr), tryptophan (Trp), and phenylalanine (Phe)) belonging to the platelet membrane have been performed. The possibility of energy transfer between Pt NPs and the platelet membrane has been revealed. Förster Resonance Energy Transfer (FRET) model was used to perform the quantitative evaluation of energy transfer parameters. The prospects of Pt NPs usage deals with quenching-based sensing for pathology's based on platelet conformations as cardiovascular diseases have been demonstrated.

This paper explores the evolution of research collaboration networks in the 'stakeholder theory and management' (STM) discipline and identifies the longitudinal effect of co-authorship networks on research performance, i.e., research productivity and citation counts. Research articles totaling 6,127 records from 1989 to 2020 were harvested from the Web of Science Database and transformed into bibliometric data using Bibexcel, followed by applying social network analysis to compare and analyze scientific collaboration networks at the author, institution and country levels. This work maps the structure of these networks across three consecutive sub-periods (t1: 1989-1999; t2: 2000-2010; t3: 2011-2020) and explores the association between authors' social network properties and their research performance. The results show that authors collaboration network was fragmented all through the periods, however, with an increase in the number and size of cliques. Similar results were observed in the institutional collaboration network but with less fragmentation between institutions reflected by the increase in network density as time passed. The international collaboration had evolved from an uncondensed, fragmented and highly centralized network, to a highly dense and less fragmented network in t3. Moreover, a positive association was reported between authors' research performance and centrality and structural hole measures in t3 as opposed to ego-density, constraint and tie strength in t1. The findings can be used by policy makers to improve collaboration and develop research programs that can enhance several scientific fields. Central authors identified in the networks are better positioned to receive government funding, maximize research outputs and improve research community reputation. Viewed from a network's perspective, scientists can understand how collaborative relationships influence research performance and consider where to invest their decision and choices.

AIMS:This study aims to test the association between the place-provider-matrix (PPM) of bystander cardiopulmonary resuscitation (CPR) and outcomes of out-of-hospital cardiac arrest (OHCA). METHODS:Adult patients with OHCA with a cardiac etiology from 2012 to 2017 in Korea were analyzed, excluding patients who had unknown information on place, type of bystander, or outcome. The PPM was categorized into six groups by two types of places (public versus home) and three types of providers (trained responder (TR), family bystander, and layperson bystander). Outcomes were survival to discharge and good cerebral performance category (CPC) of 1 or 2. Multivariable logistic regression analysis was performed to test the association between PPM group and outcomes with adjustment for potential confounders to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) (reference = Public-TR). RESULTS:A total of 73,057 patients were analyzed and were categorized into Public-TR (0.6%), Home-TR (0.3%), Public-Family (1.8%), Home-Family (79.8%), Public-Layperson (9.9%), and Home-Layperson (7.6%) groups. Compared with the Public-TR group, the AORs (95% CIs) for survival to discharge were 0.61 (0.35-1.05) in the Home-TR group, 0.85 (0.62-1.17) in the Public-Family group, 0.38 (0.29-0.50) in the Home-Family group, 1.12 (0.85-1.49) in the Public-Layperson group, and 0.42 (0.31-0.57) in the Home-Layperson group. The AORs (95% CIs) for good CPC were 0.58 (0.27-1.25) in the Home-TR group, 0.88 (0.61-1.27) in the Public-Family group, 0.38 (0.28-0.52) in the Home-Family group, 1.20 (0.87-1.65) in the Public-Layperson group, and 0.42 (0.30-0.59) in the Home-Layperson group. CONCLUSION:The OHCA outcomes of the Home-Family and Home-Layperson groups were worse than those of the Public-TR group. This finding suggests that OHCA occurring in private places with family or layperson bystanders requires a new strategy, such as dispatching trained responders to the scene to improve CPR outcomes.

Cerebral white-matter hyperintensities (WMHs) on MRI is associated with reduced compliance of the cerebral arterioles. We hypothesized that an echocardiography index for left ventricular (LV) diastolic function, E/e', might reflect the cerebral arteriolar compliance and evaluated the association between E/e' and long-term progression rate of the cerebral WMH volume. This retrospective study included individuals who were ≥ 50 years of age, with a preserved LV ejection fraction (≥ 50%) and neurological function status (modified Rankin scale score ≤1), and underwent initial and follow-up MRI evaluations within intervals of 34-45 months. Baseline clinical, laboratory, and echocardiography markers such as ejection fraction, LV mass index, and E/e' were obtained. WMH volume progression rate between the baseline and follow-up MRIs was designated as the outcome factor. 392 individuals (57.1% men; mean age: 66.7±8.4 years) were followed-up for 38.2±3.4 months. The mean WMH volume progression rate was 1.35±2.65 mL/year. The log-transformed value of WMH volume progression rate was linearly associated with the log-transformed E/e' (B coefficient = 0.365; 95% confidence interval [CI] 0.180-0.551; P = 0.001), along with the log-transformed values of baseline WMH volume (B = 0.142; 95% CI 0.106-0.179; P

[This corrects the article DOI: 10.1371/journal.pone.0194552.].

Cryolipolysis has been considered as a noninvasive alternative to surgical procedures for reducing subcutaneous fat without affecting the surrounding tissues. However, no clinical trial has investigated changes in the abdominal fat tissue by 12 weeks after cryolipolysis. Therefore, in this split-body trial, we explored whether a single session of unilateral cryolipolysis could change visceral and subcutaneous adipose tissue over a period of 12 weeks. We compared the cross-sectional areas of the abdominal adipose tissue of 15 subjects (9 women; 38.3 [10.8] years) by computed tomography before and at 12 weeks after a single treatment of cryolipolysis to the left abdomen and used the right abdomen as untreated control. In addition, we measured participants' waist circumference, percentage of body fat (by bioelectrical impedance analysis) at baseline and at 6- and 12-weeks post-treatment. Single unilateral cryolipolysis tended to reduce the cross-sectional areas of visceral adipose tissue, by 8.4 cm2 (9.9%), the waist circumferences, and the percent body fat, by 2.8 cm2 (0.6%), overall. The cross-sectional area of visceral adipose tissues on the treated side significantly decreased, by 6.8 cm2 (15.6%; P = 0.003), and that of the untreated side tended to decrease by 1.2 cm2 (3.6%). Thus, a single unilateral session of noninvasive selective cryolipolysis can be considered as a safe and effective treatment for reduction of visceral adipose tissue over a period of 12 weeks, which should result in metabolic improvement.

Type 2 diabetes (T2D) is characterised by β-cell damage and hyperglycaemia. The lipophilic drug, probucol, has shown significant β-cell protective and potential antidiabetic effects, which were enhanced by hydrophilic bile acid incorporation using taurocholic acid and chenodeoxycholic acid. However, probucol has severe cardiotoxicity and a variable absorption profile, which limit its potential applications in T2D. Accordingly, this study aimed to design multiple formulations to optimise probucol oral delivery in T2D and test their effects on probucol absorption and accumulation in the heart. Adult male mice were given a high fat diet (HFD), and a week later, injected with a single dose of alloxan to accelerate T2D development, and once diabetes confirmed, divided into three groups (six to seven mice each). The groups were gavaged a daily dose of probucol powder, probucol microcapsules, or probucol-bile acid microcapsules for three months, and euthanized; and blood, tissues, and feces collected for blood glucose and probucol concentration analyses. Probucol concentrations in plasma were similar among all the groups. Groups given probucol microcapsules and probucol-bile acid microcapsules showed significant reduction in probucol accumulation in the heart compared with the group given probucol powder (p

The inflammatory response is considered a defence mechanism against physical or infectious insults and is prevalent within the central nervous system. Seizures also result in a robust inflammatory cascade, leading to enhanced activation of excitatory synaptic networks. Ample evidence based on animal models of epilepsy has demonstrated that celecoxib, a highly selective inhibitor of cyclooxygenase-2, has anticonvulsant effects. We aimed to evaluate the impact of celecoxib on the cortical excitability and electrophysiological properties of the brain in healthy humans. Electroencephalography (EEG) or transmagnetic stimulation (TMS) was used to measure neurophysiological activity. Forty healthy volunteers were randomized to 4 groups (n = 10 in each group): 1) celecoxib and EEG, 2) placebo and EEG, 3) celecoxib and TMS, and 4) placebo and TMS. For the EEG study, resting EEG was performed at baseline just before administering 400 mg of celecoxib or placebo and repeated 4 hours after administration. The subjects took 200 mg of celecoxib or placebo twice a day for 7 subsequent days, and a third EEG was conducted 4 hours after the final dose. Power spectra were compared at each time point. For the TMS study, the resting motor threshold (RMT), motor evoked potential (MEP) peak-to-peak amplitude, and cortical silent period (CSP) were measured at baseline and after taking 200 mg of celecoxib or placebo twice a day for 7 days. Celecoxib did not significantly change brain activity in the EEG study. However, the sum of power recorded from all electrodes tended to increase in the celecoxib group only at 4 hours after administration (p = 0.06). In detail, one dose of celecoxib (400 mg) transiently and significantly increased the alpha band power recorded in the frontal and parietal areas as well as in the whole brain (p = 0.049, 0.017, and 0.014, respectively) and the beta frequency in the central and parietal regions (p = 0.013 and 0.005, respectively), whereas the placebo did not. This effect was abolished after 7 days of treatment. In the TMS study, we found no statistically significant change in the RMT, MEP peak-to-peak amplitude or CSP. This evidence suggests that celecoxib transiently alters the electrophysiological properties of the brain but does not suppress neuronal excitability in healthy humans.

Developmental anomalies of the thyroid gland lead to congenital malformations such as thyroglossal duct cysts and thyroid dysgenesis. However, the pathogenesis of thyroid dysgenesis remains unclear due to the lack of suitable animal models. This study demonstrated that Slc:Wistar/ST rats frequently developed unilateral thyroid dysgenesis, including hemiagenesis, characterized by the absence of one lobe. In Wistar/ST rats, each thyroid lobe was frequently different in size, and approximately 27% and 20% of the rats presented with hemihypoplasia and hemiagenesis of the thyroid gland, respectively. Dysgenesis was predominant on the left side in both sexes, without sex differences. At a young age, thyroid hemiagenesis did not alter body weight. In rats of both sexes with thyroid hemiagenesis, plasma total triiodothyronine and total triiodothyronine levels remained unchanged while plasma thyroid-stimulating hormone levels were significantly elevated in young rats. The remaining thyroid lobes increased in weight, but the follicular epithelial cells appeared normal in terms of their height and proliferating activities. On the side of thyroid dysgenesis, the parathyroid glands were normally localized and were situated at the same location as the contralateral glands. The ultimobranchial body remnants were localized at the level of the thyroid gland along with the cranial thyroid artery and vein, forming cell clusters or cystic structures and containing calcitonin-positive C-cells. In conclusion, Wistar/ST rats developed unilateral thyroid dysgenesis and may be novel and useful animal models for thyroid hemiagenesis in humans and for morphogenesis of pharyngeal pouch-derived organs.

ObjectivesPostmicturition dribble (PMD) is a very common symptom in males with lower urinary tract symptoms (LUTS) worldwide, but there is no adequate questionnaire to assess it. Therefore, we developed a questionnaire named the Hallym Post Micturition Dribble Questionnaire (HPMDQ) to assess PMD, and the aim of this study is to validate it.MethodsA series of consecutive male patients newly diagnosed with LUTS and over 40 years of age who visited any of 5 medical institutions were included. LUTS were assessed in all patients using the International Prostate Symptom Score (IPSS), and PMD was assessed using the HPMDQ.ResultsIn total, 2134 male patients aged 40 to 91 years were included in this study. Of these patients, 1088 (51.0%) reported PMD. In the PMD group, the mean values for HPMDQ-Q1, HPMDQ-Q2, HPMDQ-Q3 and HPMDQ total score were 1.39, 1.10, 1.76 and 4.25, respectively. In the non-PMD group, the mean values of these scores were 0, 0.18, 1.52 and 1.58, respectively. The difference in HPMDQ scores between the 2 groups was statistically significant. PMD was significantly associated with the voiding symptoms of LUTS, prostate size and postvoid residual but not with storage symptoms.ConclusionsThe HPMDQ, which consists of 5 questions (frequency, severity, bother, quality of life and response to treatment for PMD), was developed, and its use for assessing PMD is validated in this study. It may be a useful tool for further research and in clinical practice for PMD.

ImportanceCIS to MS conversion rates vary depending on population cohorts, initial manifestations, and durations of follow-up.ObjectiveTo investigate conversion rate of patients from CIS to MS and the prognostic significance of demographic and clinical variables in Taiwanese population.DesignNationwide, prospective, multi-centric, observational study from November 2008 to November 2014 with 4 years follow-up.SettingMulti-centre setting at 5 institutions in Taiwan.Participants152 patients having single clinical event potentially suggestive of MS in last 2 years were enrolled as consecutive sample. 33 patients were lost to follow-up and 16 patients did not complete the study.103 patients completed the study.Intervention(s) (for clinical trials) or exposure(s) (for observational studies)Natural progression from first episode of CIS to MS or NMO was observed.Main outcome(s) and measure(s)Variables analysed were 'proportion of patients converting to MS or NMO after first episode of CIS', 'duration between first episode of neurological event and diagnosis of MS', 'status of anti-AQP4 IgG' and 'length of longest contiguous spinal cord lesion in MS patients'. Association between baseline characteristics and progression to MS from CIS was analyzed using multiple logistic regression. Multivariate time dependent effect of baseline characteristics on progression to MS was plotted.Results14.5% patients with CIS converted to MS after 1.1 ± 1.0 years with greater predisposition (18.8%) in those having syndromes referable to the cerebral hemispheres. Conversion rate from ON to MS was 9.7%. 90.9% patients had mild disease course. 46.7% patients had abnormal MRIs at baseline, with 0.6±0.5 contrast enhanced lesions. 'Below normal BMI' and 'MRI lesion load (≥ 4 lesions)' were identified as risk indicators for the development of MS. Amongst the patients who developed NMO as diagnosed by modern criteria, 80% were positive for anti-AQP4 IgG antibody.Conclusions and relevance'Below normal BMI' and 'number of demyelinating lesions (≥4)' are significant predictors of conversion from CIS to MS. A low conversion rate to MS in Taiwanese CIS patients and majority of them having a mild course and minimal disability suggest the roles of geographic, genetic and ethnic factors.Trial registrationNon-trial observational study.

The ability to determine the origin of soybeans is an important issue following the inclusion of this information in the labeling of agricultural food products becoming mandatory in South Korea in 2017. This study was carried out to construct a prediction model for discriminating Chinese and Korean soybeans using Fourier-transform infrared (FT-IR) spectroscopy and multivariate statistical analysis. The optimal prediction models for discriminating soybean samples were obtained by selecting appropriate scaling methods, normalization methods, variable influence on projection (VIP) cutoff values, and wave-number regions. The factors for constructing the optimal partial-least-squares regression (PLSR) prediction model were using second derivatives, vector normalization, unit variance scaling, and the 4000-400 cm-1 region (excluding water vapor and carbon dioxide). The PLSR model for discriminating Chinese and Korean soybean samples had the best predictability when a VIP cutoff value was not applied. When Chinese soybean samples were identified, a PLSR model that has the lowest root-mean-square error of the prediction value was obtained using a VIP cutoff value of 1.5. The optimal PLSR prediction model for discriminating Korean soybean samples was also obtained using a VIP cutoff value of 1.5. This is the first study that has combined FT-IR spectroscopy with normalization methods, VIP cutoff values, and selected wave-number regions for discriminating Chinese and Korean soybeans.

Circular RNAs (circRNAs) involve in the epigenetic regulation and its major mechanism is the sequestration of the target micro RNAs (miRNAs). We hypothesized that circRNAs might be related with the pathophysiology of chronic epilepsy and evaluated the altered circRNA expressions and their possible regulatory effects on their target miRNAs and mRNAs in a mouse epilepsy model. The circRNA expression profile in the hippocampus of the pilocarpine mice was analyzed and compared with control. The correlation between the expression of miRNA binding sites (miRNA response elements, MRE) in the dysregulated circRNAs and the expression of their target miRNAs was evaluated. As miRNAs also inhibit their target mRNAs, circRNA-miRNA-mRNA regulatory network, comprised of dysregulated RNAs that targets one another were searched. For the identified networks, bioinformatics analyses were performed. As the result, Forty-three circRNAs were dysregulated in the hippocampus (up-regulated, 26; down-regulated, 17). The change in the expression of MRE in those circRNAs negatively correlated with the change in the relevant target miRNA expression (r = -0.461, P

BACKGROUND:Recently, sublingual immunotherapy (SLIT) has been used as a safe and efficient method for the treatment of and immunization against asthma and various allergies. However, the routes of antigen/allergen (particulate antigen) uptake through the mucosa of the oral cavity remain incompletely understood, as do the roles of sex and age in the process. For this purpose, to elucidate the mechanism and efficacy of SLIT among different sexes and ages, microbeads were dripped into the sublingual region to mimic particulate antigen uptake by the sublingual mucosa. METHODS:Twenty microliters of either phosphate buffered saline (PBS) or fluorescently labelled microbeads (latex and silica beads) were placed under the tongue of both male and female C57BL/6 mice at young (3 months) and old (6 months) ages. The lower jaw was examined 30 min after administration, and beads were detected with a fluorescence stereomicroscope. Morphological observations of the mucosa of the fluorescent areas were made with a scanning electron microscope (SEM) and an all-in-one light fluorescence microscope (LM). Fluorescence intensity was compared between both sexes and ages. RESULTS:Stereomicroscopic observation revealed fluorescent illuminations in three compartments of the sublingual mucosa: the sublingual caruncles (SC), the oral rostral mucosa (OR) and the buccal mucosa (BM). Interestingly, the fluorescence intensity tended to be higher among females than among males in the SC region in particular. However, there were no significant age-related differences. SEM and LM revealed beads in the lumina of both mandibular ducts and sublingual ducts (Sd). Additionally, the apical cytoplasm of some Sd cells contained silica beads. However, there was no specification in the OR mucosa or BM. CONCLUSIONS:This study reveals the major role Sd plays in local immunity via the antigen uptake mechanisms. Furthermore, our data suggest that the efficacy of SLIT in humans could be affected by sex.

Gemcitabine is a principal chemotherapeutic agent for biliary tract cancer (BTC). Expression of human equilibrative nucleoside transporter 1 (hENT1) is regarded as a potential predictive biomarker for a gemcitabine response in some cancers. This study was conducted to investigate the association between hENT1 expression and the effects of gemcitabine on BTC cell lines and on patients with advanced BTC receiving gemcitabine-based chemotherapy. A total of four BTC cell lines, HuCCT1, SNU-478, SNU-1079, and SNU-1196, were tested. mRNA and protein expression levels of hENT1 were measured by quantitative reverse-transcription polymerase chain reaction and western blotting, respectively. Cell viability after gemcitabine treatment was measured in a chemosensitivity assay. For clinical assessment, 40 patients with unresectable or recurrent BTC who were treated with gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) between June 2012 and May 2014 were enrolled. Among the four cell lines, SNU1196 showed the highest mRNA and protein levels of hENT1. Expression of hENT1 showed a linear correlation with the log value of the half-maximal inhibitory concentration of gemcitabine. During incubation with gemcitabine, pretreatment with hENT1-specific small interfering RNA (siRNA) resulted in higher cell viability than that in samples pretreated with control siRNA. In a clinical evaluation, the median progression-free survival was 24 and 11 weeks among patients with strong and weak intratumoral hENT1 immunohistochemical staining (P = 0.05), and the median overall survival was 52 and 26 weeks (P = 0.15), respectively. In conclusion, this study showed that increased hENT1 expression is associated with a stronger toxic effect of gemcitabine on BTC cell lines. The clinical outcomes in this study suggest that increased intratumoral hENT1 immunohistochemical staining is a possible biomarker predicting better therapeutic effects of gemcitabine on patients with advanced BTC. Further studies are needed to determine the precise role of hENT1 in BTC.

Levetiracetam (LEV) is effective for focal and generalized epilepsy and is used worldwide because of its relatively few drug interactions and favorable tolerability. However, some psychiatric adverse events (PAEs) have been reported, resulting in drug withdrawal. The pathophysiology of LEV-induced PAE has not yet been elucidated. In this study, we investigated the relationship between PAEs and human leukocyte antigen (HLA) genes. Eleven epilepsy patients, who developed PAEs after the administration of LEV and spontaneously improved after drug withdrawal, were enrolled retrospectively. Genomic DNA from the peripheral blood was extracted, and four-digit allele genotyping of HLA genes was performed. The genotype frequencies of HLA genes were compared to those of 80 patients in which LEV was well tolerated, as well as to 485 individuals from the general Korean population. The frequency of the HLA-A*1101 allele was significantly higher in the LEV-induced PAEs group compared to both the LEV-tolerant group (p = 0.021, OR 4.80, 95% CI 1.30-17.74) and the general Korean population (p = 0.015, OR 4.62, 95% CI 1.38-15.45). This study is the first attempt at investigating the relationship between the HLA system and LEV-induced PAE. The results of this study suggest that the HLA-A*1101 allele could be a risk factor for the development of PAEs.

MRL/MpJ mice have abundant ovarian mast cells (MCs) as compared with other strains at postnatal day 0 (P0); however, they sharply decrease after birth. These ovarian MCs, particularly beneath the ovarian surface epithelium (SE), which express mucosal MC (MMC) marker, might participate in early follicular development. This study investigated the changes in spatiotemporal distribution of MCs in the perinatal MRL/MpJ mouse ovaries. At P0 to P7, the MCs were densely localized to the ovary, especially their caudomedial region around the ovary-fimbria connection. The neonatal ovarian MCs showed intermediate characteristics of MMC and connective tissue MC (CTMC), and the latter phenotype became evident with aging. However, the expression ratio of the MMC to CTMC marker increased from P0 to P4 in the MRL/MpJ mouse ovary. Similarly, the ratio of MCs facing SE to total MC number increased with aging, although the number of ovarian MCs decreased, indicating the relative increase in MMC phenotypes in the early neonatal ovary. Neither proliferating nor apoptotic MCs were found in the MRL/MpJ mouse ovaries. The parenchymal cells surrounding MCs at ovary-fimbria connection showed similar molecular expression patterns (E-cadherin+/Foxl2-/Gata4+) as that of the ovarian surface epithelial cells. At P2, around the ovary-fimbria connection, c-kit- immature oocytes formed clusters called nests, and some MCs localized adjacent to c-kit- oocytes within the nests. These results indicated that in postnatal MRL/MpJ mice, ovarian MCs changed their distribution by migrating toward the parenchymal cells composing ovary-fimbria connection, which possessed similar characteristics to the ovarian surface epithelium. Thus, we elucidated the spatiotemporal alterations of the ovarian MCs in MRL/MpJ mice, and suggested their importance during the early follicular development by migrating toward the ovary-fimbria connection. MRL/MpJ mice would be useful to elucidate the relationship between neonatal immunity and reproductive systems.

Seizure clustering is a common and significant phenomenon in patients with epilepsy. The clustering of spontaneous recurrent seizures (SRSs) in animal models of epilepsy, including mouse pilocarpine models, has been reported. However, most studies have analyzed seizures for a short duration after the induction of status epilepticus (SE). In this study, we investigated the detailed characteristics of seizure clustering in the chronic stage of a mouse pilocarpine-induced epilepsy model for an extended duration by continuous 24/7 video-EEG monitoring. A seizure cluster was defined as the occurrence of one or more seizures per day for at least three consecutive days and at least five seizures during the cluster period. We analyzed the cluster duration, seizure-free period, cluster interval, and numbers of seizures within and outside the seizure clusters. The video-EEG monitoring began 84.5±33.7 days after the induction of SE and continued for 53.7±20.4 days. Every mouse displayed seizure clusters, and 97.0% of the seizures occurred within a cluster period. The seizure clusters were followed by long seizure-free periods of 16.3±6.8 days, showing a cyclic pattern. The SRSs also occurred in a grouped pattern within a day. We demonstrate that almost all seizures occur in clusters with a cyclic pattern in the chronic stage of a mouse pilocarpine-induced epilepsy model. The seizure-free periods between clusters were long. These findings should be considered when performing in vivo studies using this animal model. Furthermore, this model might be appropriate for studying the unrevealed mechanism of ictogenesis.

BACKGROUND:MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. METHODS:Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational age-matched birth weight percentile,

The impact of obesity on survival is known to vary in different cancers. Advanced biliary tract cancer was rarely analyzed about the relationship between obesity and prognosis. We performed this study to evaluate the BMI and body weight change as prognostic factors for advanced biliary tract cancer patients with palliative chemotherapy.Between January 2005 and December 2016, two hundred and seventy-six patients who underwent chemotherapy for biliary tract cancer were retrospectively analyzed. The relationship between BMI (kg/m2) and clinical outcomes including overall and progression-free survival was assessed. Additionally the relationship between change in body composition and overall survival was evaluated.Median overall survival was 9.7 months for underweight patients, 10.1 months for normal patients, 15.8 months for overweight group, 13.1 months for obese patients, respectively. (p = 0.047) Univariate analysis showed that BMI, stage III, age less than 64 year-old, gallbladder cancer, operation, radiotherapy and ECOG performance were significantly associated with better survival. Compared with normal patients, overweight patients (BMI 23-24.9kg/m2) had a reduced risk of mortality in multivariate analysis (HR 0.632; 95% CI 0.436-0.918, p = 0.016). In the additional analysis for the effect of changes in body weight and BMI to the overall survival, decrease in body weight and BMI (HR 1.410, 95% CI 1.168-1.986, p = 0.046) was associated with a shorter in overall survival.Overweight status and the maintenance of body weight during the initial period of chemotherapy are important and independent predictors of better overall survival in advanced biliary tract cancer patients.

Rhinovirus infection is associated with the majority of asthma exacerbations. The role of fractalkine in anti-viral (type 1) and pathogenic (type 2) responses to rhinovirus infection in allergic asthma is unknown. To determine whether (1) fractalkine is produced in airway cells and in peripheral blood leucocytes, (2) rhinovirus infection increases production of fractalkine and (3) levels of fractalkine differ in asthmatic compared to non-asthmatic subjects. Fractalkine protein and mRNA levels were measured in bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMCs) from non-asthmatic controls (n = 15) and mild allergic asthmatic (n = 15) subjects. Protein levels of fractalkine were also measured in macrophages polarised ex vivo to give M1 (type 1) and M2 (type 2) macrophages and in BAL fluid obtained from mild (n = 11) and moderate (n = 14) allergic asthmatic and non-asthmatic control (n = 10) subjects pre and post in vivo rhinovirus infection. BAL cells produced significantly greater levels of fractalkine than PBMCs. Rhinovirus infection increased production of fractalkine by BAL cells from non-asthmatic controls (P

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is commonly used to obtain tissue external to the gastrointestinal tract. EUS-FNA is relatively safe, but occasionally adverse events have been reported. There is scarcity of data on risk factors of adverse events. The aim of this study is to identify risk factors associated with EUS-FNA.In this multicenter case-control study, we retrospectively reviewed 4,097 cases between 2009 and 2012 at 15 hospitals in Korea. Among the patients there were 104 cases (2.5%) who had adverse events of which 12 (0.29%) were severe. We matched 520 controls (1:5 ratios) stratified by hospital to analyze the potential risk factors.The most common adverse events were pancreatitis (45/104, 43.3%) and infection (46/104, 44.2%). Endoscopic retrograde cholangiopancreatography (ERCP) on the same day was a risk factor of all adverse events [OR = 2.41, 95% CI (1.41, 4.12)], pancreatitis [OR = 2.31, 95% CI (1.02, 5.25)], and infection [OR = 2.75, 95% CI (1.31, 5.78)]. More than 15 to-and-fro movements during puncture increased the risk of pancreatitis [OR = 2.30, 95% CI (1.11, 4.77)] and infection [OR = 3.65, 95% CI (1.55, 8.59)]. A higher number of punctures was positively correlated with pancreatitis [OR = 1.34, 95% CI (1.08, 1.67)] but negatively correlated with infection [OR = 0.66, 95% CI (0.48, 0.89)].EUS-FNA is a safe procedure in which serious adverse events are rare. We define some risk factors of adverse events during EUS-FNA, including ERCP on the same day, a higher number of punctures, and more than 15 to-and-fro movements.

The short-term blood pressure variability (BPV) reflects autonomic regulatory mechanisms. However, the influence of BPV in orthostatic intolerance (OI) is unknown. Herein, we assessed BPV profiles in patients with OI and determined their association with orthostatic symptoms. In this cross-sectional study, we prospectively enrolled 126 patients presenting with OI at the Seoul National University Hospital from December 2014 to August 2016. Among them, those with other neurological diseases (n = 8) and insufficient BP measurements (n = 15) were excluded. The degree of OI symptoms were measured using the self-administered orthostatic intolerance questionnaire (OIQ). All patients underwent ambulatory BP monitoring and we calculated the standard deviation and coefficient of variation as a measure of BPV. The mean age was 48.6 years and the average of the total OIQ score was 11.6. The severe OI group had higher BPV values than the mild group, although mean BP profiles did not differ significantly. Correlation analysis demonstrated that the orthostatic symptoms were positively correlated with diastolic BPV for the total and awake periods. Multiple linear regression analysis revealed that diastolic BPV (B = 0.46, p = 0.031) and current smoking (B = 4.687, p = 0.018) were independent factors for higher OI symptom scores after adjusting for covariates. The results of the current study demonstrated that a positive correlation exists between BPV and OI symptoms. Further studies are required to confirm the present findings and understand the neural mechanisms contributing to the excessive BPV in patients with OI.

Angiogenic peptides have therapeutic potential for the treatment of chronic ischemic diseases. Periostin, an extracellular matrix protein expressed in injured tissues, promotes angiogenesis and tissue repair. We previously reported that in vivo administration of both recombinant full-length protein and the first FAS I domain of periostin alleviated peripheral artery occlusive disease by stimulating the migration of humane endothelial colony forming cells (ECFCs) and subsequent angiogenesis. In the present study, we ascertained the peptide sequence responsible for the periostin-induced angiogenesis. By serial deletion mapping of the first FAS I domain, we identified a peptide sequence (amino acids 142-151) of periostin for stimulation of chemotactic migration, adhesion, proliferation and endothelial tube formation of human ECFCs in vitro. Chemotactic migration of ECFCs induced by the periostin peptide was blocked by pre-incubation with an anti-β5 integrin neutralizing antibody. Treatment of ECFCs with the periostin peptide led to phosphorylation of both AKT and ERK, and pretreatment of ECFCs with the MEK-ERK pathway inhibitor U0126 or the PI3K-AKT pathway inhibitors, LY294002 or Wortmannin, blocked the periostin peptide-stimulated migration of ECFCs. These results suggest that the synthetic periostin peptide can be applied for stimulating angiogenic and therapeutic potentials of ECFCs.

Anticancer agents and operating procedures have been developed for hepatocellular carcinoma (HCC) patients, but their prognosis remains poor. It is necessary to develop novel diagnostic and therapeutic strategies for HCC to improve its prognosis. Lactosome is a core-shell-type polymeric micelle, and enclosing labeling or anticancer agents into this micelle enables drug delivery. In this study, we investigated the diagnostic and therapeutic efficacies of indocyanine green (ICG)-loaded lactosome for near-infrared fluorescence (NIF) imaging and photodynamic therapy (PDT) for HCC.The human HCC cell line HuH-7 was treated with ICG or ICG-lactosome, followed by PDT, and the cell viabilities were measured (in vitro PDT efficiency). For NIF imaging, HuH-7 cells were subcutaneously transplanted into BALB/c nude mice, followed by intravenous administration of ICG or ICG-lactosome. The transplanted animals were treated with PDT, and the antineoplastic effects were analyzed (in vivo PDT efficiency).PDT had toxic effects on HuH-7 cells treated with ICG-lactosome, but not ICG alone. NIF imaging revealed that the fluorescence of tumor areas in ICG-lactosome-treated animals was higher than that of contralateral regions at 24 h after injection and thereafter. PDT exerted immediate and continuous phototoxic effects in the transplanted mice treated with ICG-lactosome.Our results demonstrate that ICG-lactosome accumulated in xenograft tumors, and that PDT had antineoplastic effects on these malignant implants. NIF imaging and PDT with ICG-lactosome could be useful diagnostic and/or therapeutic strategies for HCC.

Cerebral white matter hyperintensities (WMHs) are central MRI markers of the brain aging process, but the mechanisms for its progression remain unclear. In this study, we aimed to determine whether the baseline serum cystatin C level represented one mechanism underlying WMH progression, and whether it was associated with the long-term progression of cerebral WMH volume in MRI. 166 consecutive individuals who were ≥50 years of age and who underwent initial/follow-up MRI evaluations within an interval of 34-45 months were included. Serum cystatin C level, glomerular-filtration rate (GFR), and other laboratory parameters were measured at their initial evaluation and at the end of follow-up. Cerebrovascular risk factors, medications, and blood-pressure parameters were also reviewed. WMH progression rate was measured by subtracting WMH volume at baseline from that at the follow-up using volumetric analysis, divided by the MRI intervals. At baseline, WMH volume was 9.61±13.17 mL, mean GFR was 77.3±22.8 mL/min, and mean cystatin C level was 0.92±0.52 mg/L. After 37.9±3.4 months, the change in WMH volume was 3.64±6.85 mL, the progression rate of WMH volume was 1.18±2.28 mL/year, the mean ΔGFR was 2.4±7.9 mL/min, and the mean Δcystatin C was 0.03±0.34 mg/L. The progression rate of WMH volume was linearly associated with cystatin C level (B coefficient = 0.856; 95% confidence interval [CI] 0.174-1.538; P = 0.014), along with the baseline WMH volume (B = 0.039; 95% CI 0.019-0.059; P

Emerging evidence has suggested that hydrogen sulfide (H2S) may alleviate the cellular damage associated with cerebral ischemia/reperfusion (I/R) injury. In this study, we assessed using 1H-magnetic resonance imaging/magnetic resonance spectroscopy (1H-MRI/MRS) and histologic analysis whether H2S administration prior to reperfusion has neuroprotective effects. We also evaluated for differences in the effects of H2S treatment at 2 time points. 1H-MRI/MRS data were obtained at baseline, and at 3, 9, and 24 h after ischemia from 4 groups: sham, control (I/R injury), sodium hydrosulfide (NaHS)-30 and NaHS-1 (NaHS delivery at 30 and 1 min before reperfusion, respectively). The total infarct volume and the midline shift at 24 h post-ischemia were lowest in the NaHS-1, followed by the NaHS-30 and control groups. Peri-infarct volume was significantly lower in the NaHS-1 compared to NaHS-30 and control animals. The relative apparent diffusion coefficient (ADC) in the peri-infarct region showed that the NaHS-1 group had significantly lower values compared to the NaHS-30 and control animals and that NaHS-1 rats showed significantly higher relative T2 values in the peri-infarct region compared to the controls. The relative ADC value, relative T2 value, levels of N-acetyl-L-aspartate (NAA), and the NAA, glutamate, and taurine combination score (NGT) in the ischemic core region at 24 h post-ischemia did not differ significantly between the 2 NaHS groups and the control except that the NAA and NGT values were higher in the peri-infarct region of the NaHS-1 animals at 9 h post-ischemia. In the ischemic core and peri-infarct regions, the apoptosis rate was lowest in the NaHS-1 group, followed by the NaHS-30 and control groups. Our results suggest that H2S treatment has neuroprotective effects on the peri-infarct region during the evolution of I/R injury. Furthermore, our findings indicate that the administration of H2S immediately prior to reperfusion produces the highest neuroprotective effects.

Kveim-reagent (Kv) skin testing was a historical method of diagnosing sarcoidosis. Intradermal injection of treated sarcoidosis spleen tissue resulted in a granuloma response at injection site by 4-6 weeks. Previous work indicates proteins as the possible trigger of this reaction. We aimed to identify Kv-specific proteins and characterise the ex vivo response of Peripheral Blood Mononuclear Cells (PBMCs) from sarcoidosis, tuberculosis and healthy control patients when stimulated with both Kv and selected Kv-specific proteins.Kv extracts were separated by 1D-SDS-PAGE and 2D-DIGE and then underwent mass spectrometric analysis for protein identification. Sarcoidosis and control PBMCs were first stimulated with Kv and then with three selected recombinant protein candidates which were identified from the proteomic analysis. PBMC secreted cytokines were subsequently measured by Multiplex Cytokine Assay.We observed significantly increased IFN-γ and TNF-α secretion from Kv-stimulated PBMCs of sarcoidosis patients vs. PBMCs from healthy volunteers (IFN-γ: 207.2 pg/mL vs. 3.86 pg/mL, p = 0.0018; TNF-α: 2375 pg/mL vs. 42.82 pg/mL, p = 0.0003). Through proteomic approaches we then identified 74 sarcoidosis tissue-specific proteins. Of these, 3 proteins (vimentin, tubulin and alpha-actinin-4) were identified using both 1D-SDS-PAGE and 2D-DIGE. Data are available via ProteomeXchange with identifier PXD005150. Increased cytokine secretion was subsequently observed with vimentin stimulation of sarcoidosis PBMCs vs. tuberculosis PBMCs (IFN-γ: 396.6 pg/mL vs 0.1 pg/mL, p = 0.0009; TNF-α: 1139 pg/mL vs 0.1 pg/mL, p

Current therapies for depression consist primarily of pharmacological agents, including antidepressants, and/or psychiatric counseling, such as psychotherapy. However, light therapy has recently begun to be considered as an effective tool for the treatment of the neuropsychiatric behaviors and symptoms of a variety of brain disorders or diseases, including depression. One methodology employed in light therapy involves flickering photic stimulation within a specific frequency range. The present study investigated whether flickering and flashing photic stimulation with light emitting diodes (LEDs) could improve depression-like behaviors in a corticosterone (CORT)-induced mouse model of depression. Additionally, the effects of the flickering and flashing lights on depressive behavior were compared with those of fluoxetine. Rhythmical flickering photic stimulation at alpha frequencies from 9-11 Hz clearly improved performance on behavioral tasks assessing anxiety, locomotor activity, social interaction, and despair. In contrast, fluoxetine treatment did not strongly improve behavioral performance during the same period compared with flickering photic stimulation. The present findings demonstrated that LED-derived flickering photic stimulation more rapidly improved behavioral outcomes in a CORT-induced mouse model of depression compared with fluoxetine. Thus, the present study suggests that rhythmical photic stimulation at alpha frequencies may aid in the improvement of the quality of life of patients with depression.

Inhalation anesthetics are used to decrease the spinal cord transmission of painful stimuli. However, the molecular or biochemical processes within cells that regulate anesthetic-induced responses at the cellular level are largely unknown. Here, we report the phosphoproteome profile of SH-SY5y human neuroblastoma cells treated with sevoflurane, a clinically used anesthetic. Phosphoproteins were isolated from cell lysates and analyzed using two-dimensional gel electrophoresis. The phosphorylation of putative anesthetic-responsive marker proteins was validated using western blot analysis in cells treated with both sevoflurane and isoflurane. A total of 25 phosphoproteins were identified as differentially phosphorylated proteins. These included key regulators that signal cytoskeletal remodeling steps in pathways related to vesicle trafficking, axonal growth, and cell migration. These proteins included the Rho GTPase, Ras-GAP SH3 binding protein, Rho GTPase activating protein, actin-related protein, and actin. Sevoflurane and isoflurane also resulted in the dissolution of F-actin fibers in SH-SY5y cells. Our results show that anesthetics affect the phosphorylation of proteins involved in cytoskeletal remodeling pathways.

HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection.

OBJECTIVE:To evaluate the seizure characteristics and outcome after immunotherapy in adult patients with autoimmune encephalitis (AE) and new-onset seizure. METHODS:Adult (age ≥18 years) patients with AE and new-onset seizure who underwent immunotherapy and were followed-up for at least 6 months were included. Seizure frequency was evaluated at 2-4 weeks and 6 months after the onset of the initial immunotherapy and was categorized as "seizure remission", "> 50% seizure reduction", or "no change" based on the degree of its decrease. RESULTS:Forty-one AE patients who presented with new-onset seizure were analysed. At 2-4 weeks after the initial immunotherapy, 51.2% of the patients were seizure free, and 24.4% had significant seizure reduction. At 6 months, seizure remission was observed in 73.2% of the patients, although four patients died during hospitalization. Rituximab was used as a second-line immunotherapy in 12 patients who continued to have seizures despite the initial immunotherapy, and additional seizure remission was achieved in 66.6% of them. In particular, those who exhibited partial response to the initial immunotherapy had a better seizure outcome after rituximab, with low adverse events. CONCLUSION:AE frequently presented as seizure, but only 18.9% of the living patients suffered from seizure at 6 months after immunotherapy. Aggressive immunotherapy can improve seizure outcome in patients with AE.

The goal of this study was to quantitatively assess the changes in the cerebral neurochemical profile and to identify those factors that contribute to the alteration of endogenous biomolecules when rats are subjected to stress-induced sleep disturbance. We exposed Sprague-Dawley rats (controls: n = 9; stress-induced sleep perturbation rats: n = 11) to a psychological stressor (cage exchange method) to achieve stress-induced sleep perturbation. In vivo magnetic resonance imaging assessments were carried out using a high-resolution 9.4 T system. For in vivo neurochemical analysis, a single voxel was localized in the right dorsal hippocampal region, and in vivo spectra were quantified for 17 cerebral neurochemical signals. Rats were sacrificed upon completion of the magnetic resonance spectroscopy protocol, and whole-brain tissue was harvested from twenty subjects. The dopamine and serotonin signals were obtained by performing in vitro liquid chromatography-tandem mass spectrometry on the harvested tissue. In the right dorsal hippocampal region, the gamma-aminobutyric-acid (GABA) and glutamine (Gln) concentrations were significantly higher in the sleep-perturbed rats than in the sham controls. The ratios of Gln/Glu (glutamate), Gln/tCr (total-creatine), and GABA/Glu were also significantly higher in the sleep-perturbed group, while serotonin concentrations were significantly lower in the sleep-perturbed rats. Pearson correlation results among individual rat data indicate that concentrations of dopamine (DA) and serotonin (5-HT) were significantly higher in SSP rats. A larger correlation coefficient was also observed for the SSP rats. Analysis of the correlation between the in vivo and in vitro signals indicated that the concentrations of Gln, 5-HT, and DA exhibited a significant negative correlation in the SSP rat data but not in that of control rats. The authors propose that the altered and correlated GABA, Gln, 5-HT, and DA concentrations/ratios could be considered key markers of neurological function in animal models of stress-induced sleep perturbation.

BACKGROUND:A small group of patients with inherited neuropathy that has been shown to be caused by mutations in the BSCL2 gene. However, little information is available about the role of BSCL2 mutations in inherited neuropathies in Taiwan. METHODOLOGY AND PRINCIPAL FINDINGS:Utilizing targeted sequencing, 76 patients with molecularly unassigned Charcot-Marie-Tooth disease type 2 (CMT2) and 8 with distal hereditary motor neuropathy (dHMN), who were selected from 348 unrelated patients with inherited neuropathies, were screened for mutations in the coding regions of BSCL2. Two heterozygous BSCL2 mutations, p.S90L and p.R96H, were identified, of which the p.R96H mutation is novel. The p.S90L was identified in a pedigree with CMT2 while the p.R96H was identified in a patient with apparently sporadic dHMN. In vitro studies demonstrated that the p.R96H mutation results in a remarkably low seipin expression and reduced cell viability. CONCLUSION:BSCL2 mutations account for a small number of patients with inherited neuropathies in Taiwan. The p.R96H mutation is associated with dHMN. This study expands the molecular spectrum of BSCL2 mutations and also emphasizes the pathogenic role of BSCL2 mutations in molecularly unassigned hereditary neuropathies.